Review
One year in review 2019: fibromyalgia
F. Atzeni1, R. Talotta2, I.F. Masala3, C. Giacomelli4, C. Conversano5,
V. Nucera1, B. Lucchino6, C. Iannuccelli6, M. Di Franco6, L. Bazzichi4
1
Rheumatology Unit, University of Messina;
2
Clinical Pharmacology and Toxicology,
University of Milan;
3
Orthopaedic and Trauma Unit,
Santissima Trinità Hospital, Cagliari;
4
Rheumatology Unit, Department of
Clinical and Experimental Medicine,
University of Pisa;
5
Department of Surgical, Medical
and Molecular Pathology, Critical Care
Medicine, University of Pisa;
6
Department of Internal Medicine
and Medical Specialities, Rheumatology
Unit, Sapienza University of Rome, Italy.
Fabiola Atzeni, MD, PhD
Rossella Talotta, MD, PhD
Ignazio Francesco Masala, MD
Camillo Giacomelli, PhD
Ciro Conversano, PhD
Valeria Nucera, MD
Bruno Lucchino, PhD
Cristina Iannuccelli, MD, PhD
Manuela di Franco, MD
Laura Bazzichi, MD
Please address correspondence to:
Prof. Fabiola Atzeni,
Rheumatology Unit,
University of Messina,
Via C. Valeria 1,
98100 Messina, Italy
E-mail: atzenifabiola@hotmail.com
Received and accepted on January 21,
2019.
Clin exp Rheumatol 2019; 37 (Suppl. 116):
S3-S10.
© Copyright Clinical and
Experimental Rheumatology 2019.
Key words: fibromyalgia
Competing interests: none declared.
Clinical and Experimental Rheumatology 2019
ABSTRACT
Fibromyalgia is characterised by
chronic pain, fatigue and functional
symptoms. Its aetiopathogenesis is still
a matter of debate, but various phar-
macological and non-pharmacological
therapies are currently available for its
treatment. We review the literature con-
cerning the most recent findings related
to the aetiopathogenesis, diagnosis,
clinical aspects and treatment of FM
published between January 2018 and
January 2019.
Aetiopathogenesis
In the time frame analysed by this re-
view, not so many new aetiopathoge-
netic hypotheses for fibromyalgia (FM)
have been formulated with respect to
other years (1). However, the focus of
the researchers in this year was on the
phenomena related to neuropathies. In
2018, Grayston et al. (2) proposed an
interesting meta-analysis on the preva-
lence of small fibre neuropathy in FM.
The researcher evaluated 935 scientific
articles and underlined the prevalence
of small fibre neuropathy (SFN) in 49%
of FM patients. This high prevalence of
SFN in FM emphasises the importance
of identifying standard methods for the
description of this neuropathy and un-
derstanding the processes leading to the
development of SFN, to achieve better
therapeutic and diagnostic strategies.
Moreover, Caro et al. (3) studied for
the first time large fibre involvement in
FM. In the past few years, several stud-
ies have pointed to a link between small
fibre neuropathy and FM, but in most of
the cases these studies did not evaluate
possible alterations in the large fibres.
The researchers included the electro-
myographic findings of 100 consecu-
tive unselected clinical patients that met
the 1990 ACR criteria for FM. After the
exclusion of FM subjects with con-
comitant clinical conditions that could
influence the findings of the EMG (for
example, family neural degenerative
conditions, diabetes mellitus, vitamin
B-12 deficiency, etc.) 55 FM subjects
remained: 29 subjects with “FM only”
and 26 subjects with FM + rheumatoid
arthritis (“FM + RA”). All subjects also
underwent skin ankle biopsy for the
determination of the epidermal nerve
fibre (ENFD). Fourteen other subjects,
without FM or RA, examined by the
same electromyograph, were chosen
as an EMG/NCS comparison group.
Ninety percent of the “FM only” sub-
jects generated a demyelinating and/or
axonal sensory-motor polyneuropathy,
and 63% had SFN (ENFD ≤7 fibres/
mm), suggesting a mixed fibre neuropa-
thy in most cases. In addition, 61% of
The “FM-only” subjects showed sug-
gestive EMG of non-myotomial axonal
motor denervation of the lower limbs,
most likely a cause of polyneuropathy,
and 41% met the criteria for “possible”
chronic inflammatory demyelinating
polyneuropathy (CIDP). Interestingly,
there was little difference in the EMG/
NCS findings between the “FM only”
and the “FM+RA” groups, while in the
comparison group no pathologic find-
ing was shown, with the only exception
of carpal tunnel syndrome. The results
highlighted by the research group show
that the electrodiagnostic characteris-
tics of polyneuropathy, muscle dener-
vation and CIDP are common in FM.
These findings are often seen to coin-
cide with SFN and are not significantly
affected by the presence of RA. These
results, besides helping to understand
the aetiopathogenesis of FM, can also
be useful for diagnostic purposes.
Diagnosis
The diagnosis of FM is still based on
patients’ reports and on clinical assess-
ment, mainly because the pathogenesis
of FM is still not well understood and
S-3
One year in review 2019: fibromyalgia / F. Atzeni et al.
because of the lack of reliable biomark-
ers of the disease. The publication of the
2010/2011 American College of Rheu-
matology (ACR) criteria for the diagno-
sis of FM superseded the traditional
1990 ACR classification criteria, ac-
cording to the identification of the mul-
ti-symptomatic nature of FM and the
difficulty of the standardisation of the
tender points exam, required in 1990
ACR criteria (4). However, subsequent
validation studies showed that in spite
of the simplification of FM diagnosis
through the application of symptom
scales, such as the widespread pain in-
dex (WPI) and the symptom severity
scale (SSS), there was a substantial mis-
classification mostly of patients with
severe regional pain disorders (5). The
misdiagnosis occurred principally be-
cause the 2010/2011 criteria did not
consider the spatial distribution of the
painful sites. Therefore, in 2016 a re-
vised set of criteria was published. This
revision introduced “generalised pain
criteria”, defined as the presence of pain
in 4 out of the 5 possible painful body
regions, which allowed the exclusion of
the regional pain syndromes from the
diagnosis of FM without losing the di-
agnostic accuracy of the criteria set (6).
Nevertheless, uncertainty and lack of
confidence in FM diagnostic criteria use
in clinical practice is still reported, es-
pecially in primary care settings (7).
The Analgesic, Anesthetic, and Addic-
tion Clinical Trial Translations Innova-
tions Opportunities and Networks
(ACTTION) public-private partnership
with the U.S. Food and Drug Adminis-
tration (FDA) and the American Pain
Society (APS) in 2013 gathered togeth-
er an international working group of cli-
nicians and basic scientists. The aim of
the working group was to address the
problem of the limited reliability and
validity of the existing diagnostic crite-
ria for chronic pain disorders in clinical
practice. Accordingly, the group initiat-
ed the ACTTION-APS Pain Taxonomy
(AAPT) initiative, to develop a diag-
nostic system that would be clinically
useful and consistent across chronic
pain disorders. The AAPT Taxonomy
considers 5 dimensions: dimension 1:
core diagnostic criteria; dimension 2:
common features; dimension 3: com-
S-4
mon medical co-morbidities; dimension
4: neurobiological, psychosocial, and
functional consequences; and dimen-
sion 5: putative neurobiological and
psychosocial mechanisms, risk factors,
and protective factors (8). Recently Ar-
nold et al., in order to address the prob-
lem of the limited reliability and validi-
ty of the existing diagnostic criteria,
published a multidimensional diagnos-
tic framework applied to FM. This is
based on the review of the existing diag-
nostic criteria, it reflects the current un-
derstanding of FM and is thought to be
useful in a practical clinical setting.
Identifying FM mainly as a pain disor-
der, the core diagnostic criteria (dimen-
sion 1) include the presence of multisite
pain, defined as the presence of pain in
6 out of 9 possible sites together with
moderate to severe fatigue or sleep
problems assessed by a health care pro-
fessional. Those must have been present
for at least 3 months. Dimension 2,
namely features that may support a di-
agnosis of FM, is identified in the ten-
derness to touch (positive tender points
exam), the dyscognition (trouble con-
centrating, forgetfulness, and disorgan-
ised or slow thinking), musculoskeletal
stiffness and environmental sensitivity
(intolerance to bright lights, loud nois-
es, perfumes and cold). A broad spec-
trum of possible comorbidities (dimen-
sion 3) has been identified as frequently
associated to FM, which includes sev-
eral somatic pain disorders, psychiatric
conditions, sleep disorders and rheu-
matic diseases. The outcomes related to
the disease, the poor quality of life and
the high indirect cost that belong to the
burden of FM are described in dimen-
sion 4. This last dimension includes the
risk factors for the disease, such as fa-
miliarity for functional chronic pain dis-
orders and environmental stressors that
may trigger the disease, e.g. early life-
time adverse events, trauma, medical
conditions and psychosocial stressors,
together with the current knowledge
about the putative pathophysiologic
mechanism that may sustain the disease
(see Pathogenesis). The AAPT taxo-
nomic approach to FM offers a system-
atic method to diagnose FM, focusing
on limited number of core diagnostic
symptoms but at the same time giving
the possibility to take into account the
many other associated symptoms that
may support the diagnosis of FM. This
could make the FM identification more
practical in clinical settings and at the
same time simplify the identification of
FM patients for research purposes (9).
The multidimensional approach to FM
definition offers undoubtedly advantag-
es in terms of current clinical practice
and of diagnosis, but considering the
heterogeneity of the disease and the
possible changes during the time of the
disease features, it may be limiting in
terms of practical management of the
single FM patient. Indeed, a recent ret-
rospective analysis of a large number of
patients included in an FM continuum
spectrum, identified 4 possible classes
of the disease. Class 1 was represented
by a mostly regional FM within the con-
test of the widespread pain while class 2
was characterised by a greater severity
of pain, a broader involvement of body
regions and several associated symp-
toms. These two classes represented the
most prevalent in the study population,
and their clinical phenotype overlaps
with the one identified by the diagnostic
criteria. Class 3 was characterised by an
increase in the level of pain compared to
the previous classes, a strict association
with sleep disorders and to the possibil-
ity of chemical sensitivity. The highest
severity of pain and of associated symp-
toms was present in class 4, which rep-
resented the “secondary FM” to other
diseases such as multiple sclerosis and
lupus, which had a high prevalence in
this class. During the follow-up, some
patients showed a tendency to progres-
sion from the lower to the higher classes
in a fairly linear fashion, although the
progression was also influenced by the
specific comorbidities and the presence
of secondary conditions. The results of
this study suggest that FM represents a
disease continuum in which the central-
ised pain becomes more centralised as
the disease progresses, and that the
characterisation of how the patients pro-
gress may improve diagnosis and con-
sequent management (10). Considering
all the issues in the current clinical diag-
nosis of FM, in the application of diag-
nostic criteria and in understanding and
possibly predicting the natural history
Clinical and Experimental Rheumatology 2019

of the disease, the lack of a reliable bio-
marker is a main unmet need in FM
management. Nonetheless, several new
acquisitions in terms of understanding
biologic modification of FM patients
have been recently reported and some
of them have the potential for future
clinical application. In recent years, bio-
marker research on biological fluid has
been enriched by the identification of
relatively new molecules of interest.
For example, peculiar miRNA profiles
on blood, saliva (11) and cerebrospinal
fluid (12) have shown the ability to di-
agnose and characterise FM. However,
the studied populations were small and
a validation on larger cohorts is needed.
The application of innovative tech-
niques of proteomic or metabolomic
analysis on the same biological fluids
offers new potentiality in biomarker
identification. Studying a large number
of different proteins in the biological
fluid gives the possibility to combine
more proteins of interest and increase
diagnostic accuracy. A proteomic analy-
sis of whole saliva performed on FM
patients, compared with healthy con-
trols, patients with migraine and pa-
tients with rheumatoid arthritis, showed
an increased expression of several pro-
teins like serotransferrin, alpha-enolase,
phosphoglycerate-mutase-I and trans-
aldolase. Performing a ROC curve
analysis, the combination of apha-eno-
lase, phosphoglycerate-mutase-I and
serotransferrin obtained a good dis-
criminative ability (AUC 0.792) (13).
Similarly, a proteomic analysis per-
formed on plasma of FM patients iden-
tified 33 differently expressed proteins
belonging to several patterns like acute-
phase reaction, Liver-X Receptor/Reti-
noid-X Receptor activation, Farnesoid-
X Receptor/Retinoid-X Receptor acti-
vation, complement and coagulation,
suggesting the existence of a plasmatic
inflammatory protein signature in FM,
which may be related to a neuroinflam-
matory process. Among the proteins
that presented an increased serum level
in FM patients, haptoglobin and fibrin-
ogen had the highest FM/control ratio,
representing two interesting possible
targets of further study on their role as
biomarkers (14). As well as proteomics,
metabolomics aims to screen a large
Clinical and Experimental Rheumatology 2019
One year in review 2019: fibromyalgia / F. Atzeni et al.
amount of different metabolites in bio-
logic fluid to identify the variation of
the metabolites contents that can repre-
sent a fingerprint of a specific condi-
tion. An interesting approach recently
described involves the metabolomic
screening of the low-molecular weight
fraction metabolites of human blood
collected by finger-stick. Using the in-
trinsic vibrational pattern of the differ-
ent molecules after absorbing infrared
light, the authors have been able to suc-
cessfully classify FM patients and dis-
criminate them from patients affected
by systemic lupus erythematosus or
rheumatoid arthritis, without misclassi-
fication. Moreover, the characteristic of
the vibrational spectra of FM patients
correlated with pain severity measured
through the revised fibromyalgia im-
pact questionnaire (FIQR). Apart from
being a promising diagnostic tool in
FM, this kind of metabolomic analysis
may be useful to identify serum metab-
olites that could be valuable as bio-
markers. In fact, the discriminating re-
gion of the vibrational spectra was
dominated by bands characteristics of
pyridine ring, tyrosine residues in pro-
teins and protein backbone, highlight-
ing the importance of aromatic and car-
boxylic acid molecules as potential bio-
markers, including tryptophan and its
metabolites (15). The role of tryptophan
and its metabolite, serotonin, in FM
pathogenesis has been supported by a
number of experimental observations
and confirmed by the common use in
FM treatment of selective serotonin
reuptake inhibitors (16). A reduced lev-
el of serum serotonin in blood sample
of women recently diagnosed with FM
compared to controls has been reported.
However, there was no relation between
the reduction of serum serotonin and
clinical manifestation, suggesting a
possible use of serotonin levels in FM
diagnosis but not in the assessment of
the disease severity (17). The investiga-
tion of neurologic abnormalities both in
the peripheral and central nervous sys-
tem have been a rich field of research in
FM. Several different groups have de-
scribed the presence of a small fibre
neuropathy in a large number of FM
patients, represented by a reduction in
dermal unmyelinated nerve fibre bun-
dles in skin biopsy, increased cold and
warm detection thresholds in quantita-
tive sensory testing and nociceptor hy-
perexcitability. The study of the small
fibre pathology through the skin biopsy
represents a promising and easily per-
formable diagnostic test that may allow
the identification of FM patients with
an underlying neuropathy and thereaf-
ter guide the therapeutic choice through
drugs that are active on the neuropathic
aspects of pain. A technique recently
applied to the successful identification
of the small fibre pathology in FM, cor-
neal confocal microscopy, is basically
an in vivo microscopy that may become
a useful and non-invasive FM diagnos-
tic test (18). The “central sensitisation”
has always been strongly implicated in
FM pathophysiology. The neuroim-
mune activation is one of the potential
mechanisms that may be involved in
the central nervous system abnormality
described in FM. Recently, a combined
research group from Sweden and the
United States demonstrated for the first
time the presence of activated glia, and
consequently of active neuroinflamma-
tion in the brain of FM patients. Using
positron emission tomography (PET)
imaging and radioligands that bind to
the 18-kDa translocator protein (TSPO),
the authors described an increased up-
take of the radioligand in FM patients’
brain, especially in the brain regions
previously implicated in FM pathology.
TSPO expression is normally low in
healthy brain tissue but is dramatically
upregulated in activated glial cells un-
der inflammatory stimuli. Moreover,
the radioligand uptake in several brain
regions correlated significantly with the
subjective fatigue score reported by FM
patients. Because it suggests a possible
association between neuroinflamma-
tion and FM, this work opens to future
researches about the role taken by acti-
vated microglia in FM with the possible
identification of diagnostic biomarkers
or therapeutic strategies (19). Unfortu-
nately, to date, none of these diagnostic
tests is sufficiently validated to be intro-
duced into clinical practice. Further
studies are needed in order to identify
the best diagnostic test that can easily
help the diagnosis and management of
FM patients.
S-5
One year in review 2019: fibromyalgia / F. Atzeni et al.
Treatment
Due to the heterogeneity of symptoms
and the poorly known pathogenesis,
the therapy of fibromyalgia (FM) still
remains a challenge for physicians. Ac-
cording to the most recent European
League Against Rheumatism (EULAR)
guidelines, once the diagnosis of FM
is made, priority should be given to
non-pharmacologic treatment (20). The
reason lies in cost-effectiveness, pa-
tient’s preference, safety and availabil-
ity. Physical exercise, having the best
profile of efficacy and safety, should be
prescribed to every patient with a diag-
nosis of FM. The efficacy of pharma-
cologic intervention has a weak level
of evidence, and, due to potential side
effects and low compliance, should be
indicated in specific cases (e.g. unre-
sponsive pain or sleep disturbances).
In the most severe situations, patients
could benefit from a multimodal thera-
peutic approach.
Pharmacological therapies
The therapeutic management of FM in-
cludes the use of drugs modulating neu-
rotransmission and acting on the pain,
emotional and reward circuits. Recent
European guidelines provided a de-
tailed list of recommended therapies ac-
cording to a review of published meta-
analyses and systematic reviews (20).
The authors evaluated the efficacy and
safety profile of several drugs, includ-
ing antidepressants, pain modulators,
hormones, anticonvulsants and muscle
relaxants. For some of them, including
amitriptyline, pregabalin and dulox-
etine, encouraging results on pain have
been reported. Other symptoms, such as
sleep disturbance, fatigue and disability,
may ameliorate at a different rate under
amitriptyline, pregabalin or serotonin-
ergic agents. On the contrary, based on
the disadvantageous profile of efficacy
and safety, the use of other compounds,
such as cyclobenzaprine, growth hor-
mone, non-steroideal anti-inflamma-
tory drugs (NSAIDs), steroids, strong
opioids and monoamino oxidase inhibi-
tors has been discouraged. Further evi-
dences on the effects of other molecules
on FM symptoms emerged from small
trials or additional reviews conduced in
the last 12 months. The antidepressant
S-6
drug mirtazapine is a central presyn-
aptic α2 adrenergic antagonist with
serotonergic and noradrenergic effects,
acting on amygdala, hippocampus,
frontostriatal circuits, cortical midline
structures and parietal cortex. This drug
increases neuronal response to positive
emotional and reward boosts, and at-
tenuates the processing of threatening
stimuli (21). In addition, mirtazapine
contrasts the effects of histamine on
H1 receptors and this confers sedative
properties that may be exploited in the
treatment of sleep disorders. A recent
systematic review aimed to evaluate the
effects of mirtazapine in FM patients
(22). Data from selected articles (three
randomised placebo-controlled trials
and one open-label trial) reported an
improvement in pain, sleep and qual-
ity of life, despite different treatment
doses and duration. Another systematic
review by the Cochrane group on the
use of mirtazapine in FM evaluated the
efficacy versus placebo in pain relief,
patient’s perception of efficacy, safety
and tolerability (23). The analysis of
data from 3 low-quality studies on
more than 500 FM patients treated for
at least 7 weeks revealed modest effica-
cy of mirtazapine over placebo in pain
relief and Patient Global Impression
of Change (PGIC), but also reported a
higher incidence of adverse events in
the mirtazapine arm, including somno-
lence, increase in serum transaminases
and weight gain.
The serotonin and norepinephrine
reuptake inhibitor antidepressant mil-
nacepram was tested in a prospective,
randomised, controlled double-blind
clinical trial in patients with FM (24).
The researchers evaluated the effects
of milnacipram titrated up to 100 mg/
daily in a group of 54 FM patients who
were randomised to receive the active
compound or placebo. After 1 month
of treatment, no significant difference
emerged between the two arms accord-
ing to conditioned pain modulation,
global pain, mechanical and thermal
thresholds, allodynia, cognition, and
tolerance.
The off-label use of gabapentin, a
γ-aminobutyric acid (GABA)-mimet-
ic drug, has given rise to noteworthy
interest in the last few years, due to
prescription in a wide set of chronic
pain diseases, including FM, although
the real effects on symptom relief are
inconclusive (25). However, in an
8-week prospective, single centre fea-
sibility study, the combined treatment
with gabapentin 900 mg/daily plus
osteopathic manipulative medicine re-
sulted in improved Wong-Baker FAC-
ES Pain Rating Scale scores, although
the Fibromyalgia Impact Questionnaire
(FIQ) score and the number of tender
points did not change significantly
from baseline (26).
A novel drug, acting as a N-methyl-d-
aspartate (NMDA) receptor modulator
and known as NYX-2925, is currently
investigated in FM patients in a phase
2 clinical trial (NCT03249103, www.
clinicaltrials.gov). The rationale for the
use of this agent lies in the role played
in neuronal plasticity as well as in the
control of learning and memory pro-
cesses, and in the promising results ob-
served in analgesia in preclinical stud-
ies (27).
Mexiletine is an anti-arrhythmic drug
that blocks in a non-selective way the
voltage-gated sodium channels. The
drug has also modulatory effects on
chronic nociception and muscle stiff-
ness. The retention rate and side effects
of mexiletine in neuropathic pain and
FM patients was evaluated in a retro-
spective cohort study (28). Mexile-
tine was prescribed at daily dosage of
150 up to 450 mg to 21 FM patients.
About 30% of patients discontinued the
treatment at 6 and 12 months, mainly
because of gastrointestinal, neurologic
and cardiac events. Although not re-
ported in this study, the risk of serious
side effects, such as QT abnormali-
ties and torsades de pointes, limits the
widespread use of this treatment in FM
patients.
The use of cannabinoids for the manage-
ment of FM has been diffuse in recent
years and some studies evidenced that
it could add some benefits in the con-
trol of accessorial symptoms, including
chronic low-back pain (29). Cannabi-
noids derive from the plant Cannabis
sativa L. and exert their effects by inter-
acting with the cannabinoid type 1 re-
ceptor (CB1-R) expressed by neuronal
cells and cannabinoid type 2 receptor
Clinical and Experimental Rheumatology 2019

(CB2-R) present on cells from the im-
mune system. Cannabis contains vari-
ous amounts of psychoactive compo-
nents, including the ∆9- tetrahydrocan-
nabinol (THC), which modulates noci-
ception, cognition and motor function
by binding CB1-R, and cannabidiol
(CBD) which acts as a CB2-R antago-
nist and a 5-hydroxytryptamine (5-HT)
receptor agonist, modulating mood and
cognition. Due to the different phar-
macodynamics of THC and CBD, a
recent randomised placebo-controlled
4-way crossover trial aimed to evaluate
the efficacy of 3 inhaled cannabinoids,
having a different chemical composi-
tion, versus placebo for the treatment
of FM (30). These drugs (Bedrocan®,
Bediol® and Bedrolite®) differ, in fact,
for the CBD/THC ratio. Testing 20 FM
patients, the authors evidenced a small
analgesic effect after a single inhala-
tion of each compound; interestingly,
CBD and THC shared synergistic phar-
macokinetics, whereas contrasted ac-
cording to pharmacodynamics and an-
algesic effects when co-administrated.
Bediol®, which has the highest content
of CBD, had the most impactful effect
on mechanic-induced pain.
Other data from a meta-analysis con-
ducted on patients treated with cannabi-
noids for non-oncologic chronic pain,
including subjects suffering from FM-
related pain, evidenced no superiority
of cannabinoids over placebo in terms
of physical or emotional functioning,
whereas low-quality evidence on the
improvement of sleep and PGIC was
reported (31).
The use of opioids in FM has shown
delusive results (32), although trama-
dol seems to moderately reduce pain
(20). Naltrexone, an opioid antagonist,
has achieved promising results in FM-
related pain due to the increase in the
endorphinergic tone related to the tran-
sient blockade of opioid receptors in
the central nervous system; and some
pilot studies evidenced a good profile
of efficacy and safety of this drug in the
FM setting (33).
Due to the great variability in clinical
expression, FM often requires com-
bined therapeutic strategies, including
both pharmacologic and non-pharma-
cologic approaches. A recent Cochrane
Clinical and Experimental Rheumatology 2019
One year in review 2019: fibromyalgia / F. Atzeni et al.
systematic review evaluated the effica-
cy (intended as a 30% or 50% improve-
ment of pain from baseline and PGIC
amelioration) and safety of drug com-
bination versus mono-therapy or place-
bo in published randomised controlled
trials on FM patients (34). The authors
selected 16 studies enrolling 1,474 pa-
tients. The most frequent combinations
of drugs included the association of
NSAIDs with benzodiazepine, amitrip-
tyline with fluoxetine, tramadol with
paracetamol, and monoamine oxidase
inhibitor with 5-hydroxytryptophan.
The combination of drugs seemed to
give a greater advantage on pain than a
single treatment alone, with only mild
side effects reported. However, the re-
sults were biased by the heterogeneity
of the study designs and variability in
sample sizes.
Non-pharmacological therapies
The non-pharmacological management
of FM has been focused on in many
studies and seems to have a stronger
impact on clinical manifestations,
symptoms and quality of life than the
pharmacologic treatment. Novel psy-
chological support therapy showing
promising results in FM includes virtu-
al reality, Basic Body Awareness Ther-
apy (BBAT), Cognitive-Behaviour
Therapy (CBT) and Group Music and
Imagery (GrpMI) intervention. Virtual
reality modulates pain perception by in-
fluencing attention, concentration and
emotions. Therefore, acting through a
mechanism that does not directly in-
volve the nociceptive pathway, virtual
reality may represent a valid additional
tool to pharmacologic prescription in
chronic pain conditions, like FM (35).
BBAT is a movement awareness train-
ing programme that teaches patients
how to correctly move in space and
time, increasing awareness of body co-
ordination. In a randomised study, 20
FM patients assigned to BBAT and fol-
lowed-up for 24 weeks showed a sig-
nificant reduction in pain and anxiety
scale scores compared to 21 controls
(36). CBT focuses on coping strate-
gies, emotional control and cognitive
psychology and has shown success-
ful results in counteracting mood dis-
orders and disability of FM patients
(37). When applied to the symptom
insomnia, an 8-week CBT has shown
to rescue grey matter atrophy observed
through magnetic resonance imaging
(MRI) in FM patients (38). Several
studies have demonstrated, in fact, that
long-lasting insomnia may reduce the
volume of the hippocampus, amyg-
dala, anterior cingulate cortex, insula,
medial frontal cortex, parahippocam-
pus, pre-frontal cortex, and thalamus.
When added to relaxation, GrpMI in-
tervention similarly showed beneficial
effects on mood and pain sensitisation
in 56 FM women enrolled in a 12-week
randomised trial (39).
Due to the chronicity of the disease,
one of the main concerns in treating
FM patients is the poor compliance
to a long-lasting treatment. Psycho-
logical support given by means of an
Internet platform proved to be an ef-
ficacious remedy for FM symptoms,
including pain, fatigue and mood dis-
orders. A randomised controlled trial
on 140 FM patients assigned or not to
Internet-delivered exposure showed
significant advantages on FM symp-
toms and a high retention rate (94%
of patients in therapy at 12-months)
(40). In addition, this strategy showed
greater cost-effectiveness than no treat-
ment, concerning both direct and indi-
rect costs in those patients achieving
positive results (41). Results on the
efficacy of Internet-delivered therapy
from 6 randomised controlled trials on
493 FM patients were reviewed by a
recent meta-analysis (42). The authors
demonstrated a significant reduction in
mood disturbances and disability at 6
months, despite no benefit in terms of
≥50% pain relief was observed com-
paring Internet-derived psychological
therapy to waiting list. Another sys-
tematic review on Internet-delivered
cognitive behaviour therapy in patients
with chronic diseases, including FM,
showed the greatest effect in anxiety
and depression symptom modulation
(43). In the near future, the implemen-
tation of mobile applications delivering
self-administered cognitive behaviour-
al treatment may further enhance the
adherence of patients to non-pharma-
cologic therapeutic programmes (44).
Physical exercise is a cornerstone in
S-7
One year in review 2019: fibromyalgia / F. Atzeni et al.
the non-pharmacologic management
of FM, however, specific interventions
and programmes are poorly defined
(45). A number of studies reported a
significant benefit of the Chinese dis-
cipline Tai Chi over aerobic exercise in
terms of mood and sleep disturbance,
disability and quality of life (46, 47).
However, physical activity does not
seem to influence pain sensitivity, the
management of which should require
the addition of a pharmacologic inter-
vention or other non-pharmacologic
approaches (48).
Both hot and cold temperature can
modulate nociception by acting on opi-
oid endogenous pain inhibitory system
and specific alternation of rhythm in
temperature (SART) stress can impair
the control of nociceptive stimuli in
rats (49). Some studies on the effects of
both cold and hot temperature exposure
have been carried out in FM patients.
Cryotherapy is widely used in sport
medicine due to the anti-inflammatory,
anti-oedema and analgesic properties.
In a study involving 60 FM participants
randomly assigned to whole body cryo-
therapy or rest, the researchers showed
reduced FIQ, visual analogic scale
(VAS) for pain and Combined Index
of Severity of Fibromyalgia (ICAF)
scores in treated patients (50). How-
ever, side effects were recorded, some
of which, including palpitations, mus-
cle stiffness, tremor, sleep disturbance
and headache, could have represented a
disease flare. Since the pharmacologic
background of the examined cohort is
not detailed, it may be hypothesised
that the combination of cryotherapy
plus tranquilliser or muscle-relaxant
agents would have improved the final
result and avoided some of the report-
ed side effects. Another randomised
trial involving 24 FM patients, part of
whom were assigned to a whole body
cryotherapy group for a total of 10 ses-
sions over a period of 8 days, reported
better scores in the Medical Outcome
Study Short Form-36 questionnaire,
evidencing an improvement in the
quality of life (51). On the other hand,
due to muscle relaxation, the applica-
tion of heat has given beneficial effects
in FM patients. In a study involving
7 FM patients daily undergoing 40°C
S-8
mud-bathing for a month, a benefit has
been registered in pain sensitisation to-
gether with an amelioration of serum
biochemical parameters such as tri-
glycerides and C-reactive protein (52).
The mechanical, chemical and ther-
mal properties of balneotherapy seem,
in fact, to alleviate pain by means of
several mechanisms. In particular, an
increase has been observed in pain
threshold mediated by the activation of
the descending inhibitory pain system
and gamma-fibres and augmented lev-
els of beta-endorphin, growth hormone
and adrenocorticotropic hormone in
FM patients undergoing balneother-
apy (53). In a randomised controlled
6-month trial, 100 patients with FM
were assigned to highly mineralised
sulphate water or tap water. VAS pain
and FIQ significantly ameliorated in
patients assigned to the first arm of
treatment at day 15th and benefits were
maintained over the follow-up period
(54). The application of muscle exer-
cise (e.g. using the Tai Chi technique)
in a warm water context, namely the
aquatic Ai-Chi programme, can repre-
sent a further tool to control pain and
ameliorate quality of life, as shown
by the results of an experimental pilot
study on 20 FM subjects (55).
The use of transcutaneous and percu-
taneous electrical nerve stimulation,
laser therapy and pulsed electro-mag-
netic fields has also been experimented
in FM subjects. A 12-week randomised
controlled trial on 108 FM women aim-
ing to investigate the analgesic effects
of the use of a Bio-Electro-Magnetic-
Energy-Regulation (BEMER) device
did not find any significant difference
compared to women assigned to a
sham device (56). Electro-magnetic
fields seem to act by increasing micro-
circulation and restoring the function
of the immune cells, however the exact
role in FM is uncertain. Similarly, the
use of low-level laser therapy added
to functional exercise failed to demon-
strate superiority to exercise alone in
pain, muscle performance, mood dis-
orders and quality of life in a double-
blind randomised clinical trial on 22
FM women (57).
On the contrary, the application of 12
sessions of laser therapy on facial mus-
cle tender points, in a randomised clini-
cal trial, showed a significant improve-
ment of pain from baseline in FM-re-
lated facial muscle tenderness, achiev-
ing similar results to the local injection
of lidocaine 2%, which, however, rep-
resents an invasive tool of pain control
(58). The use of weak magnetic field (2
Tesla) to induce neuro-modulation in
the left dorsolateral prefrontal cortex, a
brain area crucial for pain sensitisation,
has been tested in a 4-week randomised
double blind placebo-controlled trial
on 26 participants with a diagnosis of
FM, showing a significant improve-
ment in the symptom fatigue (59). The
results from a comparative study on
120 FM patients evidenced the supe-
riority of repetitive transcranial mag-
netic stimulation over regenerative
injection therapy, such as prolotherapy,
in Beck Depression Inventory (BDI)
scores and cortical functions, whereas
pain was less controlled (60). The tech-
nique is not invasive and is well toler-
ated with site discomfort and headache
reported as the most common side ef-
fects. In addition, the recent production
of portable devices for home use could
significantly ameliorate compliance to
this kind of therapy (61).
Finally, some studies have reported
that dietary changes may have a posi-
tive repercussion on muscular pain.
FM subjects often have a deficit in se-
lenium, magnesium, zinc, vitamins B
and D and proteins, and may benefit
from the intake of carnitine, anti-oxi-
dants, lactose-free and low-histamine
food and aromatic amino acids (62).
These nutrients can reduce systemic
and neuronal inflammation and restore
muscle strength. In addition, aromatic
amino acids, like tryptophan, may
normalise the level of neurotransmit-
ters associated to sleep and mood con-
trol. The addition of vitamin D 50,000
IU weekly to trazodone 25 mg a day
showed a significant improvement in
quality of life and pain perception in a
cohort of vitamin D-deficient FM pa-
tients followed up for 8 weeks (63).
According to another recent study,
the combination of a lacto-vegetarian
diet with exercise seems to represent a
more powerful means of pain control
and muscle strengthening (64).
Clinical and Experimental Rheumatology 2019

To conclude, given the wide range of
non-pharmacologic therapies avail-
able and showing promising results in
FM, physicians should be able to tai-
lor the treatment to the most prevalent
FM manifestations (pain, sleep distur-
bances, mood disorders, somatic symp-
toms). Moreover, in the near future, the
possibility to deliver psychological or
physical therapy directly at home by
means of a portable device or internet-
based platforms could significantly in-
crease the adherence to treatment and
reduce direct and indirect costs.
References
1. TALOTTA R, BAZZICHI L, DI FRANCO M et
al.: One year in review 2017: fibromyalgia.
Clin Exp Rheumatol 2017; 35 (Suppl. 105):
S6-12.
2. GRAYSTON R, CZANNER G, ELHADD K et al.:
A systematic review and meta-analysis of the
prevalence of small fiber pathology in fibro-
myalgia: Implications for a new paradigm in
fibromyalgia etiopathogenesis. Semin Arthri-
tis Rheum 2018 Aug 23.
3. CARO XJ, GALBRAITH RG, WINTER EF:
Evidence of peripheral large nerve involve-
ment in fibromyalgia: a retrospective review
of EMG and nerve conduction findings in 55
FM subjects. Eur J Rheumatol 2018; 5: 104-
10.
4. WOLFE F, CLAUW DJ, FitzCHARLES MA et
al.: The American College of Rheumatology
preliminary diagnostic criteria for fibromyal-
gia and measurement of symptom severity.
Arthritis Care Res 2010; 62: 600-10.
5. MÜLLER V, EGLE UT, KOKINOGENIS G,
LEDERBOGEN S, DURRER B, STAUBER S:
Implications of proposed fibromyalgia crite-
ria across other functional pain syndromes.
Scand J Rheumatol 2015; 44: 416-24.
6. WOLFE F, CLAUW DJ, FitzCHARLES MA et
al.: 2016 Revisions to the 2010/2011 fibro-
myalgia diagnostic criteria. Semin Arthritis
Rheum 2016; 46: 319-29.
7. HADKER N, GARY S, CHANDRAN AB, CREAN
SM, McNETT M, SILVERMAN SL: Primary
care physicians’ perceptions of the chal-
lenges and barriers in the timely diagnosis,
treatment and management of fibromyalgia.
Pain Res Manag 2011; 16: 440-4.
8. FILLINGIM RB, BRUEHL S, DWORKIN RH et
al.: The ACTTION-American Pain Society
Pain Taxonomy (AAPT): an evidence-based
and multidimensional approach to classify-
ing chronic pain conditions. J Pain 2014; 15:
241-9.
9. ARNOLD LM, BENNETT RM, CROFFORD LJ
et al.: AAPT Diagnostic Criteria for Fibro-
myalgia. J Pain 2018.
10. DAVIS F, GOSTINE M, ROBERTS B, RISKO R,
CAPPELLERI JC, SADOSKY A: Characterizing
classes of fibromyalgia within the continuum
of central sensitization syndrome. J Pain Res
2018; 11: 2551-60.
11. MASOTTI A, BALDASSARRE A, GUZZO MP,
IANNUCCELLI C, BARBATO C, DI FRANCO
Clinical and Experimental Rheumatology 2019
One year in review 2019: fibromyalgia / F. Atzeni et al.
M: Circulating microRNA profiles as liquid
biopsies for the characterization and diagno-
sis of fibromyalgia syndrome. Mol Neurobiol
2017; 54: 7129-36.
12. BJERSING JL, LUNDBORG C, BOKAREWA
MI, MANNERKORPI K: Profile of cerebrospi-
nal microRNAs in fibromyalgia. PLoS One
2013; 8: e78762.
13. CIREGIA F, GIACOMELLI C, GIUSTI L et al.:
”Putative salivary biomarkers useful to dif-
ferentiate patients with fibromyalgia. J Prot-
eomics 2019; 190: 44-54.
14. RAMÍREZ-TEJERO JA, MARTÍNEZ-LARA
E, RUS A, CAMACHO MV, DEL MORAL ML,
SILES E: Insight into the biological pathways
underlying fibromyalgia by a proteomic ap-
proach. J Proteomics 2018; 186: 47-55.
15. HACKSHAW KV, AYKAS DP, SIGURDSON GT
et al: Metabolic fingerprinting for diagnosis
of fibromyalgia and other rheumatologic dis-
orders. J Biol Chem 2018 Dec 6.
16. WALITT B, URRÚTIA G, NISHISHINYA MB,
CANTRELL SE, HÄUSER W: Selective seroto-
nin reuptake inhibitors for fibromyalgia syn-
drome. Cochrane Database Syst Rev 2015;
6: CD011735.
17. Al-NIMER MSM, MOHAMMAD TAM, ALSAK-
ENI RA: Serum levels of serotonin as a bio-
marker of newly diagnosed fibromyalgia in
women: Its relation to the platelet indices. J
Res Med Sci 2018; 23: 71.
18. MARTÍNEZ-LAVÍN M: Fibromyalgia and
small fiber neuropathy: the plot thickens!
Clin Rheumatol 2018; 37: 3167-71.
19. ALBRECHT DS, FORSBERG A, SANDSTRÖM
A et al.: Brain glial activation in fibromyalgia
– A multi-site positron emission tomography
investigation. Brain Behav Immun 2019; 75:
72-83.
20. MacFARLANE GJ, KRONISCH C, DEAN LE et
al.: EULAR revised recommendations for
the management of fibromyalgia. Ann Rheum
Dis 2017; 76: 318-28.
21. KOMULAINEN E, GLEREAN E, MESKANEN K
et al.: Single dose of mirtazapine modulates
whole-brain func-tional connectivity during
emotional narrative processing. Psychiatry
Res Neuroimaging 2017; 263: 61-9.
22. OTTMAN AA, WARNER CB, BROWN JN: The
role of mirtazapine in patients with fibromy-
algia: a systematic review. Rheumatol Int
2018; 38: 2217-24.
23. WELSCH P, BERNARDY K, DERRY S, MOORE
RA, HÄUSER W: Mirtazapine for fibromyal-
gia in adults. Cochrane Database Syst Rev
2018; 8: CD012708.
24. PICKERING G, MACIAN N, DELAGE N et
al.: Milnacipran poorly modulates pain in
patients suffering from fibromyalgia: a ran-
domized double-blind controlled study. Drug
Des Devel Ther 2018; 12: 2485-96.
25. PECKHAM AM, EVOY KE, OCHS L, COVVEY
JR: Gabapentin for Off-Label Use: Evidence-
Based or Cause for Concern? Subst Abuse
2018; 12: 117.
26. MARSKE C, BERNARD N, PALACIOS A et
al.: Fibromyalgia with Gabapentin and Os-
teopathic Manipulative Medicine: A Pilot
Study. J Altern Complement Med 2018; 24:
395-402.
27. GHOREISHI-HAACK N, PRIEBE JM, AGUADO
JD et al.: NYX-2925 Is a Novel N-Methyl-
d-Aspartate Receptor Modulator that Induces
Rapid and Long-Lasting Analgesia in Rat
Models of Neuropathic Pain. J Pharmacol
Exp Ther 2018; 366: 485-97.
28. ROMMAN A, SALAMA-HANNA J, DWIVEDI
S: Mexiletine usage in a chronic pain clinic:
indications, tolerability, and side effects.
Pain Physician 2018; 21: E573-E579.
29. YASSIN M, ORON A, ROBINSON D: Effect of
adding medical cannabis to analgesic treat-
ment in patients with low back pain related
to fibromyalgia: an observational cross-over
single centre study. Clin Exp Rheumatol
2019; 37 (Suppl. 116): S13-S20.
30. van de DONK T, NIESTERS M, KOWAL MA,
OLOFSEN E, DAHAN A, van VELZEN M: An
experimental randomized study on the anal-
gesic effects of pharmaceutical-grade canna-
bis in chronic pain patients with fibromyal-
gia. Pain 2018 Dec 20.
31. STOCKINGS E, CAMPBELL G, HALL WD et
al.: Cannabis and cannabinoids for the treat-
ment of people with chronic non-cancer pain
conditions: a systematic review and meta-
analysis of controlled and observa-tional
studies. Pain 2018; 159: 1932-54.
32. GOLDENBERG DL, CLAUW DJ, PALMER RE,
CLAIR AG: Opioid Use in Fibromyalgia: A
Cautionary Tale. Mayo Clin Proc 2016; 91:
640-8.
33. METYAS S, CHEN CL, YETER K, SOLYMAN J,
ARKFELD DG: Low Dose Naltrexone in the
Treatment of Fibromyalgia. Curr Rheumatol
Rev 2018; 14: 177-80.
34. THORPE J, SHUM B, MOORE RA, WIFFEN PJ,
GILRON I: Combination pharmacotherapy
for the treatment of fibromyalgia in adults.
Cochrane Database Syst Rev 2018; 2:
CD010585.
35. POURMAND A, DAVIS S, MARCHAK A, WHI-
TESIDE T, SIKKA N: Virtual Reality as a Clin-
ical Tool for Pain Management. Curr Pain
Headache Rep 2018; 22: 53.
36. BRAVO C, SKJAERVEN LH, ESPART A, GUI-
TARD SEIN-ECHALUCE L, CATALAN-MATA-
MOROS D: Basic Body Awareness Therapy
in patients suffering from fibromyalgia: A
randomized clinical trial. Physiother Theory
Pract 2018.
37. KASHIKAR-ZUCK S, BLACK WR, PFEIFFER
M et al.: Pilot randomized trial of integrated
cognitive-behavioral therapy and neuro-
muscular training for juvenile fibromyalgia:
The FIT Teens Program. J Pain 2018; 19:
1049-62.
38. McCRAE CS, MUNDT JM, CURTIS AF et al.:
Gray matter changes following cognitive be-
havioral therapy for patients with comorbid
fibromyalgia and insomnia: a pilot Study. J
Clin Sleep Med 2018; 14: 1595-603.
39. TORRES E, PEDERSEN IN, PÉREZ-FERNÁN-
DEZ JI: Randomized Trial of a Group Music
and Imagery Method (GrpMI) for Women
with Fibromyalgia. J Music Ther 2018; 55:
186-220.
40. HEDMAN-LAGERLÖF M, HEDMAN-LAGER-
LÖF E, AXELSSON E et al.: Internet-Deliv-
ered Exposure Therapy for Fibromyalgia: A
Randomized Controlled Trial. Clin J Pain
2018; 34: 532-42.
41. HEDMAN-LAGERLÖF M, HEDMAN-LAGER-
LÖF E, LJÓTSSON B, WICKSELL RK, FLINK I,
S-9
One year in review 2019: fibromyalgia / F. Atzeni et al.
ANDERSSON E: Cost-effectiveness and cost-
utility of internet-delivered exposure therapy
for fibromyalgia: results from a randomized,
controlled trial. J Pain 2019; 20: 47-59.
42. BERNARDY K, KLOSE P, WELSCH P, HÄUSER
W: Efficacy, acceptability and safety of In-
ternet-delivered psychological therapies for
fibromyalgia syndrome: A systematic review
and meta-analysis of randomized controlled
trials. Eur J Pain 2019; 23: 3-14.
43. MEHTA S, PEYNENBURG VA, HADJISTAV-
ROPOULOS HD: Internet-delivered cognitive
behaviour therapy for chronic health condi-
tions: a systematic review and meta-analysis.
J Behav Med 2018 Nov 1.
44. de la VEGA R, ROSET R, GALÁN S, MIRÓ J:
FIBROLINE: A mobile app for improving the
quality of life of young people with fibromy-
algia. J Health Psychol 2018; 23: 67-78.
45. ÁLVAREZ-GALLARDO IC, BIDONDE J,
BUSCH A et al.: Therapeutic validity of exer-
cise inter-ventions in the management of fi-
bromyalgia. J Sports Med Phys Fitness 2018
Oct 1.
46. WANG C, SCHMID CH, FIELDING RA et al.:
Effect of tai chi versus aerobic exercise for
fibromyalgia: comparative effectiveness ran-
domized controlled trial. BMJ 2018; 360:
k851.
47. OSTROVSKY DA: Tai Chi may be More Ef-
fective for Improving Fibromyalgia Symp-
toms Than Aerobic Exercise. Explore (NY)
2018; 14: 391-92.
48. MERRIWETHER EN, FREY-LAW LA, RAKEL
BA et al.: Physical activity is related to func-
tion and fatigue but not pain in women with
fibromyalgia: baseline analyses from the
Fibromyalgia Activity Study with TENS
(FAST). Arthritis Res Ther 2018; 20: 199.
49. ITOMI Y, TSUKIMI Y, KAWAMURA T: Im-
paired diffuse noxious inhibitory controls
in specific al-ternation of rhythm in temper-
S-10
ature-stressed rats. Eur J Pharmacol 2016;
784: 61-8.
50. RIVERA J, TERCERO MJ, SALAS JS, GIMENO
JH, ALEJO JS: The effect of cryotherapy on
fibromyal-gia: a randomised clinical trial
carried out in a cryosauna cabin. Rheumatol
Int 2018; 38: 2243-50.
51. VITENET M, TUBEZ F, MARREIRO A et al.:
Effect of whole body cryotherapy interven-
tions on health-related quality of life in fibro-
myalgia patients: A randomized controlled
trial. Complement Ther Med 2018; 36: 6-8.
52. MAEDA T, KUDO Y, HORIUCHI T, MAKINO N:
Clinical and anti-aging effect of mud-bathing
ther-apy for patients with fibromyalgia. Mol
Cell Biochem 2018; 444: 87-92.
53. GUIDELLI GM, TENTI S, DE NOBILI E, FIO-
RAVANTI A: Fibromyalgia syndrome and spa
therapy: myth or reality? Clin Med Insights
Arthritis Musculoskelet Disord 2012; 5: 19-
26.
54. FIORAVANTI A, MANICA P, BORTOLOTTI
R, CEVENINI G, TENTI S, PAOLAZZI G: Is
balneotherapy effective for fibromyalgia?
Results from a 6-month double-blind rand-
omized clinical trial. Clin Rheumatol 2018;
37: 2203-12.
55. PÉREZ DE LA CRUZ S, LAMBECK J: A new
approach towards improved quality of life in
fibromyalgia: a pilot study on the effects of
an aquatic Ai Chi program. Int J Rheum Dis
2018; 21: 1525-32.
56. MULTANEN J, HÄKKINEN A, HEIKKINEN P,
KAUTIAINEN H, MUSTALAMPI S, YLINEN J:
Pulsed electro-magnetic field therapy in the
treatment of pain and other symptoms in fi-
bromyalgia: A randomized controlled study.
Bioelectromagnetics 2018; 39: 405-13.
57. GERMANO MACIEL D, TRAJANO DA SILVA
M et al.: Low-level laser therapy combined
to functional ex-ercise on treatment of fibro-
myalgia: a double-blind randomized clinical
trial. Lasers Med Sci 2018 Jun 21.
58. de SOUZA RC, de SOUSA ET, SCUDINE KG et
al.: Low-level laser therapy and anesthetic
infiltration for orofacial pain in pa-tients
with fibromyalgia: a randomized clinical
trial. Med Oral Patol Oral Cir Bucal 2018;
23: e65-e71.
59. FITZGIBBON BM, HOY KE, KNOX LA et al.:
Evidence for the improvement of fatigue in
fibromyalgia: A 4-week left dorsolateral pre-
frontal cortex repetitive transcranial magnet-
ic stimulation randomized-controlled trial.
Eur J Pain 2018; 22: 1255-67.
60. ABD ELGHANY SE, AL ASHKAR DS, EL-
BARBARY AM et al.: Regenerative injection
therapy and repetitive transcranial magnetic
stimulation in primary fibromyalgia treat-
ment: A comparative study. J Back Musculo-
skelet Rehabil 2018 Aug 17.
61. CARVALHO F, BRIETZKE AP, GASPARIN A et
al.: Home-Based Transcranial Direct Cur-
rent Stimulation Device Development: An
Updated Protocol Used at Home in Healthy
Subjects and Fibromyalgia Patients. J Vis
Exp 2018.
62. BJØRKLUND G, DADAR M, CHIRUMBOLO S,
AASETH J: Fibromyalgia and nutrition: Ther-
apeutic possibilities? Biomed Pharmacother
2018; 103: 531-8.
63. MIRZAEI A, ZABIHIYEGANEH M, JAHED SA,
KHIABANI E, NOJOMI M, GHAFFARI S: Ef-
fects of vitamin D optimization on quality
of life of patients with fibromyalgia: A ran-
domized controlled trial. Med J Islam Repub
Iran 2018; 32: 29.
64. MARTÍNEZ-RODRÍGUEZ A, LEYVA-VELA B,
MARTÍNEZ-GARCÍA A, NADAL-NICOLÁS Y:
[Effects of lacto-vegetarian diet and stabili-
zation core exercises on body composition
and pain in women with fibromyalgia: rand-
omized controlled trial]. Nutr Hosp 2018; 35:
392-9.
Clinical and Experimental Rheumatology 2019